Abstract 4014: Connexin43 Remodeling in Septal Biopsies as a Sensitive Marker for Diagnosing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
Background: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is considered to be a desmosomal disease with a predominant right ventricular (RV) phenotype. The arrhythmogenic phenotype suggests impaired electrical characteristics. Histopathological diagnosis based on fibro-fatty replacement in septal biopsies is limited since
the septum is often not affected and
because of the focal nature of morphologic changes.
We investigated whether assessment of Connexin43 (Cx43) remodeling in septal biopsies of ARVD/C patients may contribute to diagnosis.
Methods: Left and right ventricular free wall (LVFW/RVFW) post-mortem material was obtained from 6 controls and 5 ARVD/C patients. In addition RV septal biopsies were taken from another 5 ARVD/C patients. Groups were age and sex matched. All patients fulfilled diagnostic Task Force Criteria and were screened for mutations in Plakophilin2 (PKP2), Desmoplakin (DSP), Desmoglein2 (DSG2), Desmocollin2 and Plakoglobin (JUP). Using immunofluorescence, expression and distribution of Cx43, N-Cadherin, PKP2, JUP and DSP were studied. Sirius Red staining was used to identify deposition of collagen.
Results: Genetic analysis of 10 ARVD/C patients revealed 4 mutations in PKP2 and 1 in DSG2. In 8/10 patients Cx43 expression was downregulated and heterogeneously distributed compared to controls. In contrast, expression and distribution of PKP2, DSP, N-Cadherin and also JUP, were remarkably unaffected. Alterations in expression profiles did not differ between LVFW and RVFW and importantly, were similar to those seen in RV septal biopsies. Sirius Red staining showed that the amount of fibrosis was increased compared to control (both in LV and RV).
Conclusions: Unlike alterations in mechanical junction proteins, alterations in expression of Cx43 can be observed in a high percentage of ARVD/C patients, regardless of the presence of desmosomal mutations. These changes can be detected by immunofluorescence in RVFW and LVFW as well as the septum, suggesting that this analysis in myocardial septal biopsies is a promising new additional diagnostic tool for ARVD/C.